ABSTRACT Autism Spectrum Disorder (ASD) is a common neuropsychiatric condition with largely unknown pathophysiology, but with a substantial genetic contribution. Over the last 8.5 years, the investigators in this highly successful Network have contributed significant advances in our understanding of ASD and enhanced open data and biomaterials resources for the research community via the NIMH Genetics Initiative and the AGRE resource. In our last renewal, we took an important new direction to fill a critical gap in ASD research by recruiting subjects of self-reported African ancestry (African-American; AA), a group not previously represented in ASD genetics research. We have made substantial progress on our aims and the project is in a critical phase: by obtaining a larger cohort via continued recruiting, we will be well powered to conduct the first comprehensive assessment of the coding and non-coding genome via whole genome sequencing (WGS). This proposal involving six research sites and the AGRE DCC, will systematically investigate the genetics of ASD to identify rare single nucleotide variation (SNV), structural variation (SV), and common variation contributing to ASD susceptibility in this population. Specifically, we will enrich existing resources by recruiting at least 700 AA probands and additional family members to bring our cohort to 1300 AA probands. We have successfully conducted a health disparities project that that confirms significant diagnostic delays despite well-articulated parental concerns. In the next phase, we propose to improve early diagnosis, facilitated by the application of a novel heritable, quantitative biomarker, which we hypothesize will improve access to care. We will leverage acquisition of WGS of all family members via other funding sources, at no cost to this proposal, to characterize the contributions of genetic risk for ASD in AA individuals, including novel rare risk variants for ASD, which will also benefit genetic studies outside of this population by improving classification of rare variation in ASD in European (EU) and other ethnicities. We will use innovative methods to define local ancestry to ascertain the background on which susceptibility alleles occur. We will perform analysis of rare de novo and transmitted variants, and perform gene-based burden tests, which are well powered in this cohort. Gene expression profiling, eQTL, and network analysis will be used to prioritize variants. Genetic risk factors identified in cohorts studied to date (EU) will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size that provides power to replicate previous associations and identify rare, recurrent CNV and SNV. We will perform follow up GWA on ASD-related endophenotypes or covariates, such as sex and social responsiveness. The observation of new forms or different population frequencies of ASD-related variation in this sample, or alternatively, the sharing of most variation with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, all data will be shared on a rolling basis, further enhancing this genetic resource for the community. .